XY Gonadal Dysgenesis Unexpectedly Identified by Direct-to-Consumer Genetic Testing

By Will Boggs MD

October 16, 2020

NEW YORK (Reuters Health) - A 16-year-old female was unexpectedly identified by direct-to-consumer (DTC) genetic testing to have XY gonadal dysgenesis and subsequently diagnosed with metastatic dysgerminoma, according to a case report.

"Physicians need to be cognizant of the 'good, bad, and ugly' of DTC genetic testing - what it does and does not offer, and its limitations," Dr. Meilan M. Rutter from Cincinnati Children's Hospital Medical Center in Ohio told Reuters Health by email. "Any test result or clinical question should be confirmed in a certified lab, and physicians should reach out to genetic counselors if faced with questions or genetic results on their patients."

Several concerns have been raised about DTC genetic testing, including uncertainty regarding the extent and implications of information that might be revealed, the lack of informed consent before test initiation, the shortage of genetic counseling support, and inadequate protection of patient privacy.

Dr. Rutter and colleagues report the case of a 16-year-old female who presented to her pediatrician because of primary amenorrhea and a surprising result from DTC commercial genetic testing, which she had been given for her birthday to learn about her ancestry.

The results from 23andMe reported an unexpected male sex, leading the pediatrician to order a karyotype, which was confirmed as 46,XY with positive SRY (sex-determining region Y) gene fluorescence in situ hybridization.

The diagnosis of this rare genetic difference of sex development (DSD) led to further evaluation, because the abnormal development of gonadal tissue results in the risk of malignant transformation of gonadal cells that remain in situ (early removal of gonads is typically recommended when patients are diagnosed with DSD).

In this otherwise healthy individual, MRI, CT, and PET scans revealed a 14-cm pelvic mass with metastases to the pelvic and paraaortic lymph nodes and both lungs. Ultrasound-guided biopsy of the pelvic mass ultimately resulted in a diagnosis of stage IV dysgerminoma.

She was treated with 2 cycles of chemotherapy, interval resection of the tumor, followed by 2 more cycles of chemotherapy, to which she had an excellent response, with radiographic resolution of the metastases and undetectable tumor markers, according to the online report in Pediatrics.

At her follow-up visit 7 months after her cancer diagnosis, the patient had completed chemotherapy, and estrogen replacement was initiated.

The patient and her family underwent psychoeducation that included differentiating between sex chromosomes, gender identity, and sexual orientation. The patient also received outpatient counseling and oncology psychosocial services.

She has remained free of recurrent tumor during posttreatment surveillance.

"On the plus side, our patient is grateful that her condition was discovered through DTC genetic testing and feels that this saved her life," Dr. Rutter said. "On the flip side, nothing could have prepared her for the simultaneous discovery that she had chromosomes that didn't match her body and the manner in which she found this out. Her case highlights the need for properly informed consent and access to genetic counseling when it comes to any kind of genetic - including DTC - testing."

"When caring for someone who has a DSD, the main message is the importance of an interdisciplinary team of specialists," she said. "In our patient's case, the DSD aspects could have easily taken a back seat to her tumor management, and yet are equally important to address at the outset. While each member of the team plays an important role, a key player is the psychologist who has expertise in DSD."

Dr. Yuk Him Tam from The Chinese University of Hong Kong, who has reviewed the tumor risk of children with XY gonadal dysgenesis, told Reuters Health by email, "I had never thought of this condition being diagnosed incidentally by DTC genetic testing. The condition is definitely rare. The reported cases were usually diagnosed when a young female adolescent presented to her GP or pediatrician with primary amenorrhea or as an incidental finding when a female infant received genetic tests to work up for other congenital anomalies not related to sex development."

"I think the availability and popularity of DTC genetic testing vary significantly from country to country, region to region," he said. "Like in Hong Kong where I live, I am not aware of any DTC genetic testing that would diagnose disease. At most, people here go for DTC genetic testing just for confirming paternity."

"Interdisciplinary DSD teams should be involved early in the gonadal management of individuals affected by this condition," Dr. Tam said.

SOURCE: https://bit.ly/3nXcatw Pediatrics, online October 15, 2020.